New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

Salina, Elena G.; Ryabova, O. B.; Kaprelyants, Arseny S.; Makarov, Vadim

doi:10.1128/aac.01308-13

Cited by 39 publications

(55 citation statements)

References 26 publications

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“…This work describes a promising new molecule, a 2-thiopyridine derivative named 1-oxido-5-(trifluoromethyl)pyridin-2-yl thiocyanate (11026103) (Fig. 1), which is particularly active against B. cenocepacia growth and was recently shown to be effective against Mycobacterium tuberculosis (10). This compound was selected after a screening of Ͼ60 compounds, which were tested against B. cenocepacia strain J2315.…”

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confidence: 99%

Mechanism of Resistance to an Antitubercular 2-Thiopyridine Derivative That Is Also Active against Burkholderia cenocepacia

Scoffone

Spadaro

Udine

et al. 2014

Antimicrob Agents Chemother

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The discovery of new compounds that are able to inhibit the growth of Burkholderia cenocepacia is of primary importance for cystic fibrosis patients. Here, the mechanism of resistance to a new pyridine derivative already shown to be effective against Mycobacterium tuberculosis and to have good activity toward B. cenocepacia was investigated. Increased expression of a resistancenodulation-cell division (RND) efflux system was detected in the resistant mutants, thus confirming their important roles in B. cenocepacia antibiotic resistance.

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confidence: 99%

Mechanism of Resistance to an Antitubercular 2-Thiopyridine Derivative That Is Also Active against Burkholderia cenocepacia

Scoffone

Spadaro

Udine

et al. 2014

Antimicrob Agents Chemother

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“…A DevR inhibitor, compound 100, killed M. tuberculosis that was cultured under hypoxic conditions, but spared the bacilli when they were nonreplicating during nutrient starvation (286). A 2-thiopyridine, compound 101 , killed both replicating and nonreplicating hypoxic and nutrient-starved M. tuberculosis (287). The 2-thiopyridines were bactericidal to viable-but-not-culturable M. tuberculosis in a potassium starvation model (287).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

“…A 2-thiopyridine, compound 101 , killed both replicating and nonreplicating hypoxic and nutrient-starved M. tuberculosis (287). The 2-thiopyridines were bactericidal to viable-but-not-culturable M. tuberculosis in a potassium starvation model (287). Compound 102 , an inhibitor of pantothenate synthase (PanC, encoded by rv3602c ) killed M. tuberculosis in a nutrient starvation model, and killed M. marinum infecting zebrafish (111).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…The selectivity index (SI) then was calculated by dividing the 50% inhibitory concentration (IC 50 ) by the MIC; an SI of Ͼ10 was considered sufficient for a compound's further evaluation (11). The in vitro model of M. tuberculosis dormancy and resuscitation was described previously (12).…”

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“…Mycobacteria were incubated in the presence of different concentrations of the compound TU112 for 7 days at 37°C. Viability of mycobacteria was tested by measuring the numbers of cells recovered from a nonculturable state by most probable number (MPN) assay as described earlier (12). The difference between TU112 groups and the untreated control was significant, with a P value of Ͻ0.01.…”

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In Vitro Activity of 3-Triazeneindoles against Mycobacterium tuberculosis and Mycobacterium avium

Никоненко

Kornienko

Majorov

et al. 2016

Antimicrob Agents Chemother

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Among 230 target-synthesized indole-based compounds, seven 3-triazenoindoles showed MICs of 0.2 to 0.5 g/ml against Mycobacterium tuberculosis strain H37Rv and isoniazid-resistant human isolate CN-40. The TU112 compound was active also against a dormant form of M. tuberculosis. Some of these triazenoindoles were active against Mycobacterium avium, with MICs of 0.05 to 0.5 g/ml. The selectivity indices (SI) for M. tuberculosis and M. avium were significantly higher than 10, making these compounds acceptable for the next testing step.A series of indole-based compounds possessing antimycobacterial activity were reported during last decade (1-3), including those from our panel of Mycobacterium-targeting N-N-containing indoles synthesized according the procedure described previously (4). Here, we present a few indole agents containing three lined-up nitrogen atoms representing a series of 3-triazenoindoles and demonstrating the most prominent antimycobacterial capacities. Synthesis of the target 3-triazenoindoles was performed using 2-ethoxycarbonyl-3H-diazoindole and appropriate secondary amines (or malononitrile for the compound TU113) by the method reported earlier (5). The characteristics of the compounds are displayed in Table 1.All reagents and solvents were purchased from commercial sources and were used without further purification. The yields refer to purified products and are not optimized. Melting points were uncorrected. Infrared (IR) spectra were run as KBr disks on an IR Fourier Magna-IR 750 Nicolet spectrometer. 1 H nuclear magnetic resonance (NMR) and 13 C NMR spectra were performed on a Bruker Avance-300 and Bruker Avance-400 (300 and 400 MHz, respectively), using tetramethylsilane (TMS) as an integral standard and hexadeuterodimethyl sulfoxide (DMSO-d6) and CDC1 as solvents. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br); chemical shifts are expressed as ␦ ppm, and the coupling constant (J) is given in hertz (Hz). Elemental analysis was performed at the laboratory of microanalysis of the A. N. Nesmeyanov Institute of Organoelement Compounds, Moscow, Russia. Mass spectra were recorded on Finnigan PolarisQ mass spectrometer.Mycobacterium tuberculosis strain H37Rv, a clinical isolate of isoniazid (INH)-resistant M. tuberculosis CN-40, and Mycobacterium avium strain 724R were obtained from the Department of Immunology of Central Institute for Tuberculosis (Moscow, Russia). The origin, storage conditions, properties, and preparation of bacterial cultures were described earlier (6-8). Initially, the compounds were tested for their capacity to inhibit [ 3 H]uracil incorporation (as preliminary screen) into M. tuberculosis H37Rv and CN-40 (4, 6), followed by MIC testing of the most active ones. MICs were determined by a standard microdilution assay using microtubes with Dubos medium containing 0.05% Tween 80. The lowest concentration of a compound resulting in no visible growth of M. tuberculosis for 2 weeks was considered the MIC (4, 9,...

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New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

Cited by 39 publications

References 26 publications

Mechanism of Resistance to an Antitubercular 2-Thiopyridine Derivative That Is Also Active against Burkholderia cenocepacia

Mechanism of Resistance to an Antitubercular 2-Thiopyridine Derivative That Is Also Active against Burkholderia cenocepacia

Targeting Phenotypically TolerantMycobacterium tuberculosis

In Vitro Activity of 3-Triazeneindoles against Mycobacterium tuberculosis and Mycobacterium avium

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